ProjectSummary/Abstract Addictionisadisease.AccordingtotheNationalInstituteonDrugAbuse,addictioncanbehereditary,andcan be triggered by environmental conditions and behavior. One key environmental factor involves the ready accesstounusedprescriptionopioidsbypotentialabusers,especiallyteens. Elysiumhasdiscoveredanovelmoleculardeactivation(XpiRx?or?expiringpill?)technologythatisdesigned toeffectivelycurbthewidespreadstockpiling,diversion,abuse,andoverdoseofunusedprescriptionopioids, even by the most common route of abuse, oral ingestion. Current opioid pills lose only <1% of their potency per year, resulting in a 70-year potency half-life. Using Elysium?s XpiRx technology, prescription opioids will provide effective analgesia to pain patients, then safely and irreversibly lose their potency after their prescribed-use period lapses, rendering them (i) unattractive to recreational and chronic abusers, and (ii) significantlylesslikelytoelicitpotentiallylethalrespiratorydepressioneffectswhenoverdosed.Broadusedof Elysium?s XpiRx technology would substantially decrease the pool of opioid drugs currently available to abusersandaddicts,andreducetheriskofoverdose. Keystakeholdershaveexpressedstronginterestintechnologiestocurtaildiversionofprescriptionopioids: TheOfficeforNationalDrugControlPolicy(ONDCP)andTheNationalInstituteonDrugAbuse(NIDA) haveidentifieddiversionasahighpriorityissuebecauseitfuelstheprescriptiondrugabuseepidemic. Pharmaceutical company leaders believe that XpiRx could become a standard safety requirement for opioiddrugs(likeairbagsforautomobiles). Experts have indicated that they are not aware of any technologies in development or on the market that addressprescriptionopioiddiversion. Under our initial SBIR Fast-Track Grant (1R44DA037908), we achieved several key milestones: (i) identified lead and backup development candidates;? (ii) discovered two proprietary strategies to achieve targeted product profiles;? (iii) demonstrated proof of concept for two potential target product profiles with life-saving potential;? (iv) generated significant commercial interest;? and (v) obtained critical feedback from the FDA. We intendtobuildonthesuccessfulprogressunderourinitialFastTrackGrantwiththisproposedSBIRPhaseIIB Continuation Grant. The overall objective of this grant proposal is to qualify a lead XpiRx immediate-release productcandidateforhumanclinicalstudiesbycompletingrequisiteIND-enablingstudies.Theseactivitieswill have a meaningful impact on advancing our lead XpiRx product candidate toward FDA approval and a commercializationdealwithalargerpharmaceuticalcompany.